ANTIMALARIAL COMPOSITIONS AND USES THEREOF
Provided herein are compounds, compositions and method of using thereof to treat or prevent malaria.
1 . A method for the treatment or prevention of malaria in a subject comprising administering to the subject a pharmaceutical suspension comprising nanoparticles or microparticles of a crystalline compound of Formula (III) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
wherein: R 11 is C 1 -C 6 alkyl.
2 . The method according to claim 1 , wherein R 11 is C 6 alkyl.
3 . The method according to claim 1 , wherein the compound of Formula (III) is
or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
4 . The method according to claim 1 , wherein the suspension comprises microparticles of a crystalline compound of Formula (III) with average particle size in the range of about 1 μm to about 50 μm.
5 . The method according to claim 1 , wherein the suspension comprises microparticles of a crystalline compound of Formula (III) with average particle size in the range of about 10 μm to about 20 μm.
6 . The method according to claim 1 , wherein the suspension further comprises a pharmaceutically acceptable excipient selected from surfactants, solubilizers, emulsifiers, preservatives, isotonicity agents, dispersing agents, wetting agents, fillers, solvents, buffers, stabilizers, lubricants, thickening agents, suspending agents, and any combinations thereof.
7 . The method according to claim 1 , wherein the suspension further comprises Synperonic® F108, dodecyl sodium sulfate (SLS), D-a-tocopheryl polyethylene glycol 1000 succinate (TPGS), hydroxypropyl methylcellulose (HPMC), and any combinations thereof.
8 . The method according to claim 1 , wherein the wherein the concentration of the crystalline compound of Formula (III) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is between about 20 mg/mL and about 300 mg/mL.
9 . The method according to claim 1 , wherein the pharmaceutical suspension is administered by subcutaneous or intramuscular injection.
10 . The method according to claim 1 , wherein the pharmaceutical suspension is effective for sustained or controlled release.
11 . The method according to claim 1 , wherein the compound of Formula (III) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is released from the pharmaceutical suspension over a period of at least about twelve weeks after administration.
12 . The method according to claim 1 , wherein the compound of Formula (III) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is released from the pharmaceutical suspension at a rate providing an average concentration of trans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione in the blood plasma of said subject of at least about 200 nM or at least about 1000 nM over about 13 weeks.
13 . The method according to claim 1 , wherein the compound of Formula (III) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is administered with an additional antimalarial agent.
14 . The method according to claim 13 , wherein the additional antimalarial agent is selected from the group consisting of artemisinin, artemisinin derivatives, proguanil, quinine, chloroquine, amodiaquine, pyrimethamine, doxycycline, clindamycin, mefloquine, primaquine, pyronaridine, halofantrine, and ELQ-300.
15 . A compound of Formula (III) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
wherein:
R 11 is C 6 alkyl.